头孢唑兰及其中间体的合成
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摘要
头孢唑兰作为高效低毒的第四代注射用头孢菌素，在治疗由细菌引起的各类疾病等临床医疗领域具有重要意义。论文对头孢唑兰及其C-3位、C-7位侧链中间体进行了合成路线和工艺条件的研究，分别合成了咪唑并[1,2-b]哒嗪和2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚胺基乙酸苯并噻唑硫酯，并与母核7-氨基头孢烷酸(7-ACA)结合，进行了头孢唑兰的全合成工作。
探索了在形成噻二唑环后引入甲氧亚胺基，合成C-7位侧链(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚胺基乙酸的方法。以丙二腈为起始原料，与HCl、甲醇进行pinner醇解反应，生成3-甲氧基-3-亚胺基丙腈。与甲醇继续反应，得到3,3,3-三甲氧基丙腈，通过对该步反应机理的研究，选择适合的工艺条件，使收率提高到85%。发现3,3,3-三甲氧基丙腈脱甲醇生成3,3-二甲氧基丙烯腈是可逆化学反应，未反应原料可循环使用。碱性条件下，3,3-二甲氧基丙烯腈与羟胺基团闭环反应得5-甲氧基-3-氨基异恶唑，经取代，成环，氧化，水解从而制得2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚胺基乙酸。与先引入甲氧亚胺基的工艺路线相比，显著提高了合成转化效率和收率。总收率提高到40%以上。
二硫化二苯并噻唑(DM)是合成多种头孢菌素C-7位侧链的保护基。论文选择无毒混合溶剂对2-巯基苯并噻唑(M)进行精制，以氧气做氧化剂，氧化氮气体为载氧剂，在流化床反应器中实现“爆晶”工艺条件，通过一步化学反应，制得初熔点达到183℃，纯度达到98.8%以上的药用DM，生产过程可实现无三废排放。
以马来酸酐为起始原料，强酸为反应介质,可显著提高马来酰肼的收率。采取一锅法合成中间体3,6-二氯哒嗪，产品收率由二步法的74.4%提高至88%。采用微波辅助合成3-氨基-6-氯哒嗪，反应时间从17小时缩短到0.5小时之内。在咪唑环形成过程中，以乙醇为溶剂，采用价格低廉的氯乙醛，简化了反应后处理过程。在6-氯咪唑并[1,2-b]哒嗪脱氯过程中,使用钯炭作催化剂,在常压下通入氢气即可得到咪唑并[1,2-b]哒嗪，各单步收率均高于80%，总收率69%，具有的工业应用价值。
以国内生产的7-ACA、自制的氨噻二唑肟乙酸苯并噻唑硫酯和咪唑并[1,2-b]哒嗪，合成出盐酸头孢唑兰，其特征参数与文献值相符合。
Cefozopran, the fourth generation of injection cephalosporins, has the advantagesof low toxicity and high activity, which played an important role in the treatment ofvarious diseases caused by bacteria in clinical medical field. This article focused onthe synthetic works of the C-3, C-7side-chains of Cefozopran, succeeded insynthesizing2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z) methoxyimino amino acid andimidazo [1,2-b] pyridazine, these two intermediates reacted with the nucleus，7-aminocephalosporanic acid (7-ACA) which produced Cefozopran, the wholesynthesis process was introduced.
This paper chooses the synthetic route which introduce methoxy imino functionalgroup after the formation of thiadiazole ring to produce the C-7side chain(Z)-2-(5-amino-1,2,4-thiadiazole oxadiazole3-yl)-2-methoxy imino acid.Malononitrile was used as the starting material and reacted with HCl and methanol toproduce3-methoxy-3-imino propionitrile. The following reaction produced3,3,3-trimethoxy-propionitrile which can loose one methanol molecule to generate3,3-dimethoxy-acrylonitrile.5-methoxy-3-amino-isoxazole was got by cyclized withhydroxylamine, with substitution reaction, cyclization, oxidation and hydrolysis toproduce (Z)-2-(5-amino-1,2,4-thiadiazole oxadiazole3-yl)-2-methoxy imino acid.Compared with the route which introduces methoxy imino route functional groupprior to the formation of thiadiazole ring, this route improved the yield and theefficiency of the reaction, total yield exceeded40%.
2,2-Dibenzothiazole, disulfide (DM) is the protecting group for the synthesis ofC-7side chains of variety of cephalosporins. This paper chose the mixed solvent torefine2-Mercaptobenzothiazole (M), used oxygen as the oxidant, nitric oxide as theoxygen carrier, produced medicine grade DM in fluidized bed reactor. The oxidationof M is a kind of free radical reaction. The mixed solvent has good solubility towardsM, DM is the only solid phase which precipitated from the reaction system. Thismixed solvent reduced the phase numbers and shorten the mass transfer path; Nitricoxide gas is the oxygen carrier which can carry oxygen between gas-liquid bi-phase toachieve rapid transmission; the application of fluidized bed reactor eliminated the reactant diffusion effects. All of the factors mentioned above in this article werecombined together, Bring in the ‘explosive crystallization of DM’ in industry. The DMwhich produced under the conditions of ‘explosive crystallization’ appeared rod-like,easy to wash, the melting point reached183°C, the purity was98.8%, in accordancewith the needs of the pharmaceutical industry.
This paper used maleic anhydride as the starting material, synthesized imidazo [1,2-b] pyridazine through hydrazinolysis, halogenation, ammonolysis, cyclization anddehalogenation. Strong acids were applied as the reaction medium in first step, theyield of maleic hydrazide can be reached up to96%.3,6-dichloro-pyridazine wassynthesized by a new one-pot method which increased the yield from74.4%to88%.3-amino-6-chloro pyridazine could be synthesized by microwave-assistedammonolysis, which could shorten the reaction time from17hours to0.5hours.During the formation of imidazole ring, with ethanol as the solvent, the use oflow-cost chloroacetaldehyde could simplify the reaction process. In the hydrogenationof the6-chloro-imidazo [1,2-b] pyridazine, palladium carbon was used as the catalyst,the reaction could be accomplished under atmospheric pressure. Since eachsingle-step yield was higher than80%, the total yield achieved69%, this syntheticroute was considered to be practical in industry.
Hydrochloric Cefozopran was synthesized by using domestic produced7-ACA,self-made (Z)-2-(5-amino-1,2,4-thiadiazole oxadiazole3-yl)-2-methoxy imino acidbenzothiazole thioesters and imidazole [1,2-b] pyridazine, which characteristicparameters were consistent with literature values.
探索了在形成噻二唑环后引入甲氧亚胺基，合成C-7位侧链(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚胺基乙酸的方法。以丙二腈为起始原料，与HCl、甲醇进行pinner醇解反应，生成3-甲氧基-3-亚胺基丙腈。与甲醇继续反应，得到3,3,3-三甲氧基丙腈，通过对该步反应机理的研究，选择适合的工艺条件，使收率提高到85%。发现3,3,3-三甲氧基丙腈脱甲醇生成3,3-二甲氧基丙烯腈是可逆化学反应，未反应原料可循环使用。碱性条件下，3,3-二甲氧基丙烯腈与羟胺基团闭环反应得5-甲氧基-3-氨基异恶唑，经取代，成环，氧化，水解从而制得2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚胺基乙酸。与先引入甲氧亚胺基的工艺路线相比，显著提高了合成转化效率和收率。总收率提高到40%以上。
二硫化二苯并噻唑(DM)是合成多种头孢菌素C-7位侧链的保护基。论文选择无毒混合溶剂对2-巯基苯并噻唑(M)进行精制，以氧气做氧化剂，氧化氮气体为载氧剂，在流化床反应器中实现“爆晶”工艺条件，通过一步化学反应，制得初熔点达到183℃，纯度达到98.8%以上的药用DM，生产过程可实现无三废排放。
以马来酸酐为起始原料，强酸为反应介质,可显著提高马来酰肼的收率。采取一锅法合成中间体3,6-二氯哒嗪，产品收率由二步法的74.4%提高至88%。采用微波辅助合成3-氨基-6-氯哒嗪，反应时间从17小时缩短到0.5小时之内。在咪唑环形成过程中，以乙醇为溶剂，采用价格低廉的氯乙醛，简化了反应后处理过程。在6-氯咪唑并[1,2-b]哒嗪脱氯过程中,使用钯炭作催化剂,在常压下通入氢气即可得到咪唑并[1,2-b]哒嗪，各单步收率均高于80%，总收率69%，具有的工业应用价值。
以国内生产的7-ACA、自制的氨噻二唑肟乙酸苯并噻唑硫酯和咪唑并[1,2-b]哒嗪，合成出盐酸头孢唑兰，其特征参数与文献值相符合。
Cefozopran, the fourth generation of injection cephalosporins, has the advantagesof low toxicity and high activity, which played an important role in the treatment ofvarious diseases caused by bacteria in clinical medical field. This article focused onthe synthetic works of the C-3, C-7side-chains of Cefozopran, succeeded insynthesizing2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z) methoxyimino amino acid andimidazo [1,2-b] pyridazine, these two intermediates reacted with the nucleus，7-aminocephalosporanic acid (7-ACA) which produced Cefozopran, the wholesynthesis process was introduced.
This paper chooses the synthetic route which introduce methoxy imino functionalgroup after the formation of thiadiazole ring to produce the C-7side chain(Z)-2-(5-amino-1,2,4-thiadiazole oxadiazole3-yl)-2-methoxy imino acid.Malononitrile was used as the starting material and reacted with HCl and methanol toproduce3-methoxy-3-imino propionitrile. The following reaction produced3,3,3-trimethoxy-propionitrile which can loose one methanol molecule to generate3,3-dimethoxy-acrylonitrile.5-methoxy-3-amino-isoxazole was got by cyclized withhydroxylamine, with substitution reaction, cyclization, oxidation and hydrolysis toproduce (Z)-2-(5-amino-1,2,4-thiadiazole oxadiazole3-yl)-2-methoxy imino acid.Compared with the route which introduces methoxy imino route functional groupprior to the formation of thiadiazole ring, this route improved the yield and theefficiency of the reaction, total yield exceeded40%.
2,2-Dibenzothiazole, disulfide (DM) is the protecting group for the synthesis ofC-7side chains of variety of cephalosporins. This paper chose the mixed solvent torefine2-Mercaptobenzothiazole (M), used oxygen as the oxidant, nitric oxide as theoxygen carrier, produced medicine grade DM in fluidized bed reactor. The oxidationof M is a kind of free radical reaction. The mixed solvent has good solubility towardsM, DM is the only solid phase which precipitated from the reaction system. Thismixed solvent reduced the phase numbers and shorten the mass transfer path; Nitricoxide gas is the oxygen carrier which can carry oxygen between gas-liquid bi-phase toachieve rapid transmission; the application of fluidized bed reactor eliminated the reactant diffusion effects. All of the factors mentioned above in this article werecombined together, Bring in the ‘explosive crystallization of DM’ in industry. The DMwhich produced under the conditions of ‘explosive crystallization’ appeared rod-like,easy to wash, the melting point reached183°C, the purity was98.8%, in accordancewith the needs of the pharmaceutical industry.
This paper used maleic anhydride as the starting material, synthesized imidazo [1,2-b] pyridazine through hydrazinolysis, halogenation, ammonolysis, cyclization anddehalogenation. Strong acids were applied as the reaction medium in first step, theyield of maleic hydrazide can be reached up to96%.3,6-dichloro-pyridazine wassynthesized by a new one-pot method which increased the yield from74.4%to88%.3-amino-6-chloro pyridazine could be synthesized by microwave-assistedammonolysis, which could shorten the reaction time from17hours to0.5hours.During the formation of imidazole ring, with ethanol as the solvent, the use oflow-cost chloroacetaldehyde could simplify the reaction process. In the hydrogenationof the6-chloro-imidazo [1,2-b] pyridazine, palladium carbon was used as the catalyst,the reaction could be accomplished under atmospheric pressure. Since eachsingle-step yield was higher than80%, the total yield achieved69%, this syntheticroute was considered to be practical in industry.
Hydrochloric Cefozopran was synthesized by using domestic produced7-ACA,self-made (Z)-2-(5-amino-1,2,4-thiadiazole oxadiazole3-yl)-2-methoxy imino acidbenzothiazole thioesters and imidazole [1,2-b] pyridazine, which characteristicparameters were consistent with literature values.
引文
[1] Waksman S A. What Is an Antibiotic or an Antibiotic Substance?Mycologia.1947,39(5):565–569.
[2] von Nussbaum F, Brands M, Hinzen B, et al. Medicinal Chemistry ofAntibacterial Natural Products–Exodus or Revival? Angew. Chem. Int. Ed.2006,45(31):5072–5129.
[3]彭司勋.药物化学，第一版，北京:中国医药科技出版社，1999，361
[4]张建藩.近年来抗生素及合成抗生素市场的研究进展.新药与市场，1989,27(1):1-7.
[5]段学民,头孢匹罗和头孢匹罗类似物及其中间体的合成,[博士学位论文],天津,天津大学,2005
[6]李瑞.药理学，第一版，北京:人民卫生出版社，1999，300.
[7] Nakayama E, Fujimoto K, Muramatsu S, et al. Cephalosporin antibiotics. I.Synthesis and structure-activity relationships of3-thiazoliomethyl derivatives. JAntibiot(Tokyo),1991,44(8):854-863.
[8] Fleming A. On the antibacterial action of cultures of a Penicillium, with specialreference to their use in the isolation of B influenzae. British Journal ofExperimental Pathology,1929,10(3):226-236.
[9] Notter A. The difficulties of industrializing penicillin (1928-1942)(AlexanderFleming, Howard Florey, Ernst Boris Chain). Histoire des sciencesmedicales.1991,25(1):31–38.
[10] Podolsky M. L. Cures Out of Chaos: How Unexpected Discoveries Led toBreakthroughs in Medicine and Health,1997, Harwood Academic
[11] Abraham E. P, Newton G. G. F. Structure of cephalosporin C. BiochemicalJournal.1961,79(2):377–393.
[12]张致平.抗生素科学的进展.中国药学杂志，1999，32(11):698-699.
[13]韩刚,蒋立建,韩冲等.新型β-内酰胺类抗生素及其特点.东南大学学报(医学版)2008，27(4):316-318.
[14]徐兆瑜.7-ADCA和7-ACA的应用和市场.化工技术经济，2004，22(4):18-23.
[15] Okita T, Imae K, Hasegawa T, et al. Synthesis and antibacterial activity ofcephalosporins having a catechol in the C3side chain. J Antibiot(Tokyo).1993,46(5):833-889.
[16]顾觉奋.抗生素的合理应用.上海:上海科学技术出版社，2004,50-60.
[17]周春艳.2位亚甲基取代的头孢菌素类新化合物的合成研究，[硕士学位论文]，天津：天津大学，2008.
[18] Foye W O, Lemke T L, Williams D A. Principles of medicinal chemistry (4thed) Baltimore: Williams&Wilkins,1995,777.
[19]尤启冬.药物化学，第二版，北京:化学工业出版社，2008，390
[20]薛哲头孢磺啶钠的合成工艺研究及新的头孢类化合物的制备，[硕士学位论文],南昌：南昌大学，2008
[21]王华.新头孢菌素头孢匹罗.国外医药:抗生素分册，1996,17(2):105-106.
[22]宋丹甲氧头孢类药物中间体7-MAC的合成研究,[硕士学位论文],大连：大连理工大学，2009
[23] Verghese A. The use of oral antibiotics in daily clinical practice. Drugs.1991,42(Suppl4):1-5.
[24]刘晓.2位取代的头孢菌素类新化合物的合成与生物活性的研究,[硕士学位论文],北京:中国协和医科大学,2008
[25]汪东海.盐酸头孢甲肟的合成工艺研究,[硕士学位论文],沈阳:沈阳药科大学,2007.
[26]戴德银，卢海波，赵俊.头孢菌素的分类、药效及临床应用现代临床医学，2007,33（S1）：81-84.
[27]张莉,匡湘红,田汉文等.头孢呋辛、头孢唑啉和氨苄西林对β-内酰胺酶稳定性的比较研究四川生理科学杂志1999,21(2):29-31.
[28]龚劭刚新型头孢菌素药物及其中间体的合成[硕士学位论文],南昌：南昌大学，2005.
[29]傅德才，狄蕊，李彬.头孢菌素类抗生素的研究进展.河北师范大学学报（自然科学版），2006，30(6):694-699.
[30]郝军香.盐酸头孢吡肟的合成研究，[硕士学位论文]，长沙：湖南师范大学，2004.
[31] Yun H C, Ellis M W, Jorgensen J H. Activity of ceftobiprole againstcommunity-associated methicillin-resistant Staphylococcus aureus isolatesrecently recovered from US military trainees. Diagnostic Microbiology andInfectious Disease.2007,59(4):463-466.
[32] Widmer A F. Ceftobiprole: A new option for treatment of skin and soft-tissueinfections due to methicillin-resistant Staphylococcus aureus. Clin Infect Dis.2008,46(5):656–658.
[33] Noel G J, Bush K, Bagchi P, et al. A randomized, double-blind trialcomparing ceftobiprole medocaril with vancomycin plus ceftazidime plusceftazidime for the treatment of patients with complicated skin and skin-structureinfections. Clin Infect Dis.2008,46(5):647–655.
[34] Hebeisen P, Heinze-Krauss I, Angehrn P, et al. In vitro and in vivo propertiesof Ro63-9141, a novel broad-spectrum cephalosporin with activity againstmethicillin-resistant staphylococci. Antimicrob Agents Chemother,2001,45(3):825–836.
[35] Thompson A.3-Basilea superbug drug approved in Canada. Reuters News,2008, June30.
[36] Forest Announces FDA Approval of Teflaro(TM)(ceftaroline fosamil) for theTreatment of Community-Acquired Bacterial Pneumonia and Acute BacterialSkin and Skin Structure Infection"(Press release). Forest Laboratories.2010-10-29.
[37] Ishikawa t, Nobuyuki M, et al. TAK-599, a novel N-phosphono type prodrugof anti-MRSA cephalosporin T-91825: Synthesis, physicochemical andpharmacological properties". Bioorg Med Chem,2003,11(11):2427–2437.
[38]蒋锦;刘秉全;郭慧元第四代头孢菌素——盐酸头孢唑兰国外医药(抗生素分册)，2006,27(2):61-68.
[39]刘书妤抗生素标准物质的溯源性研究[博士学位论文]北京：中国协和医科大学，2008.
[40]陈国华，任重，杨阳.盐酸头孢唑兰的合成.中国抗生素杂志，2009，34(8):479-480.
[41]于韬，张珂良，王晖等.盐酸头孢唑兰的合成.中国药物化学杂志,2006，16(2):91-92.
[42]川真田博康，吴澜，李建.“一锅法”制备头孢唑兰及其中间体的方法,CN200510064421.1,2006-10-18
[43] Miyake A, Yoshimura Y, Yamaoka T, et al. Studies on condensed-heterocyclicazolium cephalosporins. IV.Synthesis and antibacterial activity of7β-[2-(5-amino-1,2,4–thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-(condensed-heterocyclic azolium)methylcephalosporins. J Antibiot(Tokyo),1992,45(5):709-720.
[44] Sugiyama I, Komatsu Y, Yamauchi H. Synthesis and structure-activityrelationships of a new series of cephalosporins, E1040and related compounds[J].J Antibiot(Tokyo),1992,45(1):103-112.
[45]刘明亮，刘秉全，曹钰等.(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚胺基乙酸合成路线图解.中国医药工业杂志，2006，37(11):789-791.
[46] Teraji T, Sakane K, Goto J.2-Substitutedhydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid or its salt and theirintermediates. GB2094794,1982-09-22.
[47] Fujiwara Y, Shundo T, Fujii T. Preparation of thiadiazoleacetate crystals asmaterials for cephalosporins. JP4077477,1992-03-11.
[48] Inagaki T, Kurita Y. Preparation of syn-2-alkoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acids. JP10195064,1998-07-28.
[49] Kanai T, Takayanagi K, Tanaka Y, et al. Preparation of1,2,4-thiadiazol(alkoxyimino) acetic acids as intermediates for cephalosporins.JP62286979,1987-12-12.
[50] Kanai T, Takayanagi K, Tanaka Y, et al. Preparation of thiadiazolylacetamidederivatives as bactericide intermediates. EP62248434，1987-12-09.
[51] Sakane K, Terasawa T. Preparation of2-(substitutedhydroxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetateasantibiotic intermediates. EP413151,1991-02-2-0
[52] Goto J, Sakane K, Teraji T, et al. Studies of7β-[2-(aminoaryl)acetamido]cephalosporin derivatives.Ⅲ.Synthesis andstructure-activity relationships in the aminothiadiazole series. J Antibiot (Tokyo),1984,37(5):557-571.
[53] Tatsuta K, Miura S, Gunji H, et al. Practical preparation of (Z)-2-(5-amino-1,2,4-thiadia zol-3-yl)-2-methoxyiminoacetic acid: a side-chain of thefourth generation of cephamantibiotics. Bull Chem Soc Jpn,1994,67(6):1701-1707.
[54] Tatsuta K, Miura S, Gunji H, etal. A practical preparation of(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid. TetrahedronLett,1993,34(40):6423-6426.
[55] Tatsuta K, Kurita Y, Inagaki T, et al. Process for preparing1,2,4-thiadiazolederivatives from isoxazoles by rearrangement reaction. EP536900,1993-04-14.
[56] Sakurai A, Midorikawa H. The cyclization of ethyl cyanoacetate andsalicylaldehyde or3-methoxysalicylaldehyde with ketones by means ofammonium acetate. Bull Chem Soc Jpn,1970,43(9):2925-2933.
[57] Yamaoka M, Hashimoto N. Preparation of2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyl-or alkoxyimno)acetic acids for acylating aminogroups of cephalosporins, penicillins andazetidinones. JP62205066,1987-09-09.
[58] Ishikawa T, Iizawa Y, Okonogi K, et al. Studies on anti-MRSA parenteralcephalosporins. I. Synthesis and antibacterial activity of7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-hydroxyiminoacetamido]-3-(substituted imidazo[1,2-b] pyridazinium-1-yl)methyl-3-cephem-4-carboxylates andrelated compounds. J Antibiot (Tokyo),2000,53(10):1053-1070.
[59] Schaefer F D. Synthesis of the s-triazine system.Ⅳ.1. Preparation ofunsymmetrically substituted triazines byreaction of amidine salts with imidates. JOrg Chem,1962,27:3608-3613.
[60]郭强,刘明亮(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸的合成.中国药物化学杂志，2009，19(3):188-190.
[61]周伟斌2-甲氧亚胺-2-(5-氨基-1，2，4-噻唑-3-基)乙酸苯并噻唑硫酯的工艺研究.安徽大学学报，2007，31(6):74-77.
[62]徐景侠，头孢唑兰和头孢克定侧链酸合成研究，[硕士学位论文]，天津;天津大学，2009
[63]徐景侠，头孢唑兰和头孢克定侧链酸合成研究，安徽医药，2011，15(3)：294-295.
[64]潘小国，吴宇，张惠等.硫化促进剂DM的合成.化学推进剂与高分子材料，1998，4:38-39.
[65] Geiser J F, Hopper R J. Preparation of2.2’-dithiobis(benzothiazole) in anaqueous/alcohol reaction medium. US4755607,1988-07-05.
[66] Kaplan J H, Kinstler, R C, et.al. Continuous process for preparingbenzothiazyl disulfide. US4482720,1984-11-16.
[67] Danuta G, Jerzy, S, Jerzy W, et.al. Manufacture of2,2'-dibenzothiazolyldisulfide using N-chloro amines as oxidants. PL151594B1,1990-09-28.
[68] Gejza B.2,2'-Dibenzothiazolyl disulfide. CS18257915,1980-04.
[69] Ermakov O A, Davydova G F. Shtyrkov V N, et.al. Optimum parameters ofthe oxidative dimerization of2-mercaptobenzothiazole by hydrogen peroxide.Journal of applied chemistry of the USSR,1977,50(2):349-353.
[70] Lubomir K, Zubica M. Method of2,2-dibenzothiazolyl disulfidepreparation.CS254947B11988-11-15.
[71] Sever S, Luminita S, Mihaela B, et.al. Process for preparation of2-benzothiazolyl disulfide by oxidation of2-mercaptobenzothiazole. RO106253B1,1993-03-31.
[72] Tazuma J J. Method of preparation dibenzothiazolyl disulfides. US4463178，1984-07-31.
[73] Graeber E L, Lindstrom M J. Process for the preparation of2,2’-dithiobis(benzothiazole). US4859778,1989-04-22.
[74]陈昭琼.电解氧化制备二硫化二苯并噻唑.湘潭大学自然科学学报，1991，13(1):90-94.
[75] Nolte W, Konigshofen H, Sicheneder A. Process for preparation ofdithiazolyl disulfide. US6124467,2000-09-26.
[76] Shah S T A, Khan K M, Fecker M, et.al. A novel method for the sytheses ofsymmetrical disulfides using CsF-Celite as a solide base. Tetrahedron Letters,2003,(44):6789-6791.
[77] Zengel H G, Bergfeld M, Eisenhuth L. Process for the preparation ofdithiazolyl disulfide. US4558135,1985-12-10.
[78] Evans B J, Doi J T, Musker W K. Fluorine-19NMR study of the reaction ofp-fluorobenzenethiol and disulfide with periodate and other selected oxidizingagents, J.Org.Chem,1990,(55):2337-2377.
[79] Wolber W, Oberthür. Process for the production of dithiazolyl disulfides，US6610857,2003-08-26.
[80] Kang T W, Moon W S, Choi Y W, et.al. Preparation of reactive Phosphates ofthiazolylacetic acid as intermediates for preparing cephalosporin antibioties.WO9612712(A1),1996-05-02.
[81]王荣耕.新型活性酯DAMA.精细与专用化学品，2004，12(l3):11-12.
[82]王荣耕.氨噻肟酸与AE-活性酯.精细与专用化学品，2001，9(l):18-19.
[83]薛尧森,头孢药物中间体的合成及其配合物的研究,[硕士学位论文],青岛,中国海洋大学,2006
[84]王新杨, MICA活性硫酯工艺研究,河南师范大学学报,2009，37(6):165-167.
[85] Furlenmeier A, Hubschwerlen C N, Hofheinz W, et al. Process for thepreparation of1-sulfo-2-oxoazetidine derivatives. EP0096297,1983-12-21.
[86] Kishimoto S, Tomimatsu K, Miyake A,et al. New cephem compounds,theirproduction and use as antibiotics. EP249170,1987-12-16.
[87]高世豪，孙成辉，赵信.2-(5-氨基-1,2,4-,噻二唑-3-基)-2-(Z)-甲氧亚胺基乙酸苯并噻唑硫酯的合成工艺改进，精细化工，2007，24(8):816-819.
[88]董庆，吴松，孙颖等.二硫化二苯并噻唑在β-内酰胺合成中的应用.华西药学杂志，1990，15(1):12-14.
[89]高世豪，高长权，赵信岐.2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚胺基乙酸苯并噻唑硫酯的合成，中国医药工业杂志，2008，39(9):645-646.
[90] Ishikawa T, Iizawa Y, Okonogi K, et al. Studies on anti-MRSA parenteralcephalosporins. I. Synthesis and antibacterial activity of7-[2-(5-amino-1，2，4-thadiazol-3-yl)-2(Z)-hydroxyiminoacetamido]-3-(substituted imidazo [1，2-b]pytidazinium-1-yl)methyl-3–cephem-4-carboxylates and related compounds.Journal of Antibiotics,2000,53(10):1053-1070.
[91] Kobe J, Stanovnik B, Tisler T. Synthesis of pyridazine derivatives.XV. Someelectrophilic substitutions on imidazo [1,2-b] pyridazines. Tetrahedron,1968,24(1):239-345.
[92] Stanovnik B, Tislei M. Synthesis of imidazo [1,2-b]-s-trazolo[3′,4′-f]pyridazine, a new tricyclic azaheterocycle. Tetrahedron. Letters,1966,(22):2403-2406.
[93] Stanovnik B, Tisler M. Synthesis of pyridazine derivatives VIII. Imidazo [1,2-b] pyridazines and some tricyclic aza analogs. Tetrahedron,1967,23(1):387-395.
[94] Fabio P F, Lanzilotti A E, Lang S A. Synthesis of carbon-14and deuteriumlabeled3-nitro-6-propoxyimidazo[1,2-b]pyridazine-an antiparasitic agent. Jouralof Labelled Comounds and Radiopharmaceuticals,1978,15(Suppl.Vol.):407-412.
[95] Fajgelj S, Stanovnik B, Tisler M. Transformations of3-benzoyl-6-chloroimdazo[1,2-b]pyridazine. Vestnik Slovenskega KemijskegaDrustva,1985,32(2):137-145.
[96] Thomas D T, Charles J, Charles H.Moudlators of interleukin-1receptor-associated kinase.US2011/0021513A1,2011-01-27.
[97] Raboisson P, Mekonnen B, Peet N P. Efficient preparation of imidazo[1,2-b]pyridazines under Swern oxidative conditions. Tetrahedron Letters,2003,44(14):2919-2921.
[98]康从民，张德华，吕英涛.6-氯咪唑并[l,2-b]哒嗪的合成，化学与生物工程，2009，26(12):25-27.
[99] Stanovnik B, Ti ler M, Kunaver M, et al. Aza-transfer reactions. A novelmethod for the conversion of monosubstituted hydrazine compounds intohydrocarbons. Tetrahedron Letters,1978,19(33):3059-3062.
[100] Maeda Y, Tsukamoto T. Preparation of6-chloroimidazo[1,2-b] pyridazinehydrochloride as intermediate for cephalosporins. JP2040387，1990-02-09.
[101] Fujiwara Y,Shundo T. Preparation of6-amino-3-chloropyridazine as materialfor cephalosporins. JP4077474,1992-03-27.
[102]付春．咪唑[l，2-b]哒嗪．精细与专用化学品，2005，13(5):14-15.
[103]张连第，郭成.咪唑并[1,2-b]哒嗪的合成研究，江苏化工，2005，33(4):48-50.
[104] Miyake A, Kondo M, Fujino M.3-Condensed imidazoliumcephemcompounds. US4864022,1989-09-5.
[105] Nishimura S, Fujiwara Y, Hidaka H. Production of7-aminocephalosporanicacid derivative. WO9793002,1997-10-23.
[106] Yoshida K, Nishimura S, Maeda Y. Crystal of cephalosporin derivative andits production JP19980305664.1998-11-04.
[107]刘保起，李明华，孙松.盐酸头孢唑兰的制备方法、盐酸头孢唑兰粉针剂及其制备方法. CN10126256，2008-09-17.
[108] Padmanabhan R, Ramesh KA, Sundaravadivelan S, et al. An improvedprocess for the preparation of cefozopran: WO2009138487,2009-11-19.
[109] Miyake A, Kondo M, Fujino M, et al. Antibacterial compounds, theirproduction and use. EP0203271,1993-05-26.
[110] Teraji T, Sakane K, Goto J, et al. Cephem compounds, processes for theirpreparation and pharmaceutical compositions containing them. EP0027599,1984-10-03.
[111]龚登凰，贾国宾，武仙英等.盐酸头孢唑兰的合成研究，现代化工，2011，31(增1):110-111.
[112]郭鹏.新型降压药佐芬普利与头孢唑兰中间体7ACP的合成研究,[硕士论文]，济南；山东大学,2005.
[113]杨石,盐酸头孢唑兰及其中间体的制备方法, CN101735245A,2010-06-16.
[114]夏成才,程冬苹,于文博等.第四代头孢研究进展及合成综述,应用化工,2005,34(3):137-140.
[115] Takanohashi K, Yoshida T, Fujii S. Thiazole derivatives. US4695639,1987-09-22
[116] Hebeisen P. Process for producing allyl aminthiazole acetate intermediates.US4888429,1989-12-19
[117]陆宏国，徐云根，任东等.咪唑并［1，2-b］哒嗪的制备,中国医药工业杂志，2006,37(12):809-810.
[118] Feuer H, White E H, Wyman J E. The reactions of maleic anhydride withhydrazine hydrate. J Am Chem Soc,1958,80(14):3790-3792.
[119] Mizzoni R H, Spoerri P E. Synthesis in the pyridazine series. I. Pyridazineand3,6-dichloropyridazine. J Am Chem Soc,1951,73(4):1873-1874.
[120]蔡靖佩，许惠中.马来酰肼的合成与应用,江苏化工，1996，24(1):16-17，26.
[121] Katrusiak A，Katrusiak A. Polymorph-specific chlorination ofmaleic-hydrazide. Journal of Molecular Structure,2003,647(1-3):203-210.
[122]李荣坡.抑芽丹-马来酰肼的合成工艺研究,中国化工学会农药专业委员会第九届年会论文集:1998,9,404-406.
[123] Miyake A, Kondo M, Fujino M. Antibacterial compounds, their productionand use. WO8605183,1986-09-12.
[124]杨兰.医药中间体DM的清洁生产工艺，[硕士学位论文],青岛:青岛科技大学，2007.
[125] Dean J A.兰氏化学手册，北京：科学出版社，2003，6-11
[126]祝远娇,陈祖芬,陈小鹏等.反应-与结晶耦合单离脱氢枞酸过程研究,高校化学工程学报,2008,22(3):395-400.
[127]徐正.医药等中间体从传统向精细/专用化发展，精细与专用化学品，2005，133(4):29.
[128]周梅，陈光耀，马民.改变溶媒体系对AE活性酯合成收率及质量的影响，山东医药工业，2001，20(5):5-6.
[2] von Nussbaum F, Brands M, Hinzen B, et al. Medicinal Chemistry ofAntibacterial Natural Products–Exodus or Revival? Angew. Chem. Int. Ed.2006,45(31):5072–5129.
[3]彭司勋.药物化学，第一版，北京:中国医药科技出版社，1999，361
[4]张建藩.近年来抗生素及合成抗生素市场的研究进展.新药与市场，1989,27(1):1-7.
[5]段学民,头孢匹罗和头孢匹罗类似物及其中间体的合成,[博士学位论文],天津,天津大学,2005
[6]李瑞.药理学，第一版，北京:人民卫生出版社，1999，300.
[7] Nakayama E, Fujimoto K, Muramatsu S, et al. Cephalosporin antibiotics. I.Synthesis and structure-activity relationships of3-thiazoliomethyl derivatives. JAntibiot(Tokyo),1991,44(8):854-863.
[8] Fleming A. On the antibacterial action of cultures of a Penicillium, with specialreference to their use in the isolation of B influenzae. British Journal ofExperimental Pathology,1929,10(3):226-236.
[9] Notter A. The difficulties of industrializing penicillin (1928-1942)(AlexanderFleming, Howard Florey, Ernst Boris Chain). Histoire des sciencesmedicales.1991,25(1):31–38.
[10] Podolsky M. L. Cures Out of Chaos: How Unexpected Discoveries Led toBreakthroughs in Medicine and Health,1997, Harwood Academic
[11] Abraham E. P, Newton G. G. F. Structure of cephalosporin C. BiochemicalJournal.1961,79(2):377–393.
[12]张致平.抗生素科学的进展.中国药学杂志，1999，32(11):698-699.
[13]韩刚,蒋立建,韩冲等.新型β-内酰胺类抗生素及其特点.东南大学学报(医学版)2008，27(4):316-318.
[14]徐兆瑜.7-ADCA和7-ACA的应用和市场.化工技术经济，2004，22(4):18-23.
[15] Okita T, Imae K, Hasegawa T, et al. Synthesis and antibacterial activity ofcephalosporins having a catechol in the C3side chain. J Antibiot(Tokyo).1993,46(5):833-889.
[16]顾觉奋.抗生素的合理应用.上海:上海科学技术出版社，2004,50-60.
[17]周春艳.2位亚甲基取代的头孢菌素类新化合物的合成研究，[硕士学位论文]，天津：天津大学，2008.
[18] Foye W O, Lemke T L, Williams D A. Principles of medicinal chemistry (4thed) Baltimore: Williams&Wilkins,1995,777.
[19]尤启冬.药物化学，第二版，北京:化学工业出版社，2008，390
[20]薛哲头孢磺啶钠的合成工艺研究及新的头孢类化合物的制备，[硕士学位论文],南昌：南昌大学，2008
[21]王华.新头孢菌素头孢匹罗.国外医药:抗生素分册，1996,17(2):105-106.
[22]宋丹甲氧头孢类药物中间体7-MAC的合成研究,[硕士学位论文],大连：大连理工大学，2009
[23] Verghese A. The use of oral antibiotics in daily clinical practice. Drugs.1991,42(Suppl4):1-5.
[24]刘晓.2位取代的头孢菌素类新化合物的合成与生物活性的研究,[硕士学位论文],北京:中国协和医科大学,2008
[25]汪东海.盐酸头孢甲肟的合成工艺研究,[硕士学位论文],沈阳:沈阳药科大学,2007.
[26]戴德银，卢海波，赵俊.头孢菌素的分类、药效及临床应用现代临床医学，2007,33（S1）：81-84.
[27]张莉,匡湘红,田汉文等.头孢呋辛、头孢唑啉和氨苄西林对β-内酰胺酶稳定性的比较研究四川生理科学杂志1999,21(2):29-31.
[28]龚劭刚新型头孢菌素药物及其中间体的合成[硕士学位论文],南昌：南昌大学，2005.
[29]傅德才，狄蕊，李彬.头孢菌素类抗生素的研究进展.河北师范大学学报（自然科学版），2006，30(6):694-699.
[30]郝军香.盐酸头孢吡肟的合成研究，[硕士学位论文]，长沙：湖南师范大学，2004.
[31] Yun H C, Ellis M W, Jorgensen J H. Activity of ceftobiprole againstcommunity-associated methicillin-resistant Staphylococcus aureus isolatesrecently recovered from US military trainees. Diagnostic Microbiology andInfectious Disease.2007,59(4):463-466.
[32] Widmer A F. Ceftobiprole: A new option for treatment of skin and soft-tissueinfections due to methicillin-resistant Staphylococcus aureus. Clin Infect Dis.2008,46(5):656–658.
[33] Noel G J, Bush K, Bagchi P, et al. A randomized, double-blind trialcomparing ceftobiprole medocaril with vancomycin plus ceftazidime plusceftazidime for the treatment of patients with complicated skin and skin-structureinfections. Clin Infect Dis.2008,46(5):647–655.
[34] Hebeisen P, Heinze-Krauss I, Angehrn P, et al. In vitro and in vivo propertiesof Ro63-9141, a novel broad-spectrum cephalosporin with activity againstmethicillin-resistant staphylococci. Antimicrob Agents Chemother,2001,45(3):825–836.
[35] Thompson A.3-Basilea superbug drug approved in Canada. Reuters News,2008, June30.
[36] Forest Announces FDA Approval of Teflaro(TM)(ceftaroline fosamil) for theTreatment of Community-Acquired Bacterial Pneumonia and Acute BacterialSkin and Skin Structure Infection"(Press release). Forest Laboratories.2010-10-29.
[37] Ishikawa t, Nobuyuki M, et al. TAK-599, a novel N-phosphono type prodrugof anti-MRSA cephalosporin T-91825: Synthesis, physicochemical andpharmacological properties". Bioorg Med Chem,2003,11(11):2427–2437.
[38]蒋锦;刘秉全;郭慧元第四代头孢菌素——盐酸头孢唑兰国外医药(抗生素分册)，2006,27(2):61-68.
[39]刘书妤抗生素标准物质的溯源性研究[博士学位论文]北京：中国协和医科大学，2008.
[40]陈国华，任重，杨阳.盐酸头孢唑兰的合成.中国抗生素杂志，2009，34(8):479-480.
[41]于韬，张珂良，王晖等.盐酸头孢唑兰的合成.中国药物化学杂志,2006，16(2):91-92.
[42]川真田博康，吴澜，李建.“一锅法”制备头孢唑兰及其中间体的方法,CN200510064421.1,2006-10-18
[43] Miyake A, Yoshimura Y, Yamaoka T, et al. Studies on condensed-heterocyclicazolium cephalosporins. IV.Synthesis and antibacterial activity of7β-[2-(5-amino-1,2,4–thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-(condensed-heterocyclic azolium)methylcephalosporins. J Antibiot(Tokyo),1992,45(5):709-720.
[44] Sugiyama I, Komatsu Y, Yamauchi H. Synthesis and structure-activityrelationships of a new series of cephalosporins, E1040and related compounds[J].J Antibiot(Tokyo),1992,45(1):103-112.
[45]刘明亮，刘秉全，曹钰等.(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚胺基乙酸合成路线图解.中国医药工业杂志，2006，37(11):789-791.
[46] Teraji T, Sakane K, Goto J.2-Substitutedhydroxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid or its salt and theirintermediates. GB2094794,1982-09-22.
[47] Fujiwara Y, Shundo T, Fujii T. Preparation of thiadiazoleacetate crystals asmaterials for cephalosporins. JP4077477,1992-03-11.
[48] Inagaki T, Kurita Y. Preparation of syn-2-alkoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acids. JP10195064,1998-07-28.
[49] Kanai T, Takayanagi K, Tanaka Y, et al. Preparation of1,2,4-thiadiazol(alkoxyimino) acetic acids as intermediates for cephalosporins.JP62286979,1987-12-12.
[50] Kanai T, Takayanagi K, Tanaka Y, et al. Preparation of thiadiazolylacetamidederivatives as bactericide intermediates. EP62248434，1987-12-09.
[51] Sakane K, Terasawa T. Preparation of2-(substitutedhydroxyimino)-2-(5-amino-1,2,4-thiadiazol-3-yl)acetateasantibiotic intermediates. EP413151,1991-02-2-0
[52] Goto J, Sakane K, Teraji T, et al. Studies of7β-[2-(aminoaryl)acetamido]cephalosporin derivatives.Ⅲ.Synthesis andstructure-activity relationships in the aminothiadiazole series. J Antibiot (Tokyo),1984,37(5):557-571.
[53] Tatsuta K, Miura S, Gunji H, et al. Practical preparation of (Z)-2-(5-amino-1,2,4-thiadia zol-3-yl)-2-methoxyiminoacetic acid: a side-chain of thefourth generation of cephamantibiotics. Bull Chem Soc Jpn,1994,67(6):1701-1707.
[54] Tatsuta K, Miura S, Gunji H, etal. A practical preparation of(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetic acid. TetrahedronLett,1993,34(40):6423-6426.
[55] Tatsuta K, Kurita Y, Inagaki T, et al. Process for preparing1,2,4-thiadiazolederivatives from isoxazoles by rearrangement reaction. EP536900,1993-04-14.
[56] Sakurai A, Midorikawa H. The cyclization of ethyl cyanoacetate andsalicylaldehyde or3-methoxysalicylaldehyde with ketones by means ofammonium acetate. Bull Chem Soc Jpn,1970,43(9):2925-2933.
[57] Yamaoka M, Hashimoto N. Preparation of2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyl-or alkoxyimno)acetic acids for acylating aminogroups of cephalosporins, penicillins andazetidinones. JP62205066,1987-09-09.
[58] Ishikawa T, Iizawa Y, Okonogi K, et al. Studies on anti-MRSA parenteralcephalosporins. I. Synthesis and antibacterial activity of7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-hydroxyiminoacetamido]-3-(substituted imidazo[1,2-b] pyridazinium-1-yl)methyl-3-cephem-4-carboxylates andrelated compounds. J Antibiot (Tokyo),2000,53(10):1053-1070.
[59] Schaefer F D. Synthesis of the s-triazine system.Ⅳ.1. Preparation ofunsymmetrically substituted triazines byreaction of amidine salts with imidates. JOrg Chem,1962,27:3608-3613.
[60]郭强,刘明亮(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸的合成.中国药物化学杂志，2009，19(3):188-190.
[61]周伟斌2-甲氧亚胺-2-(5-氨基-1，2，4-噻唑-3-基)乙酸苯并噻唑硫酯的工艺研究.安徽大学学报，2007，31(6):74-77.
[62]徐景侠，头孢唑兰和头孢克定侧链酸合成研究，[硕士学位论文]，天津;天津大学，2009
[63]徐景侠，头孢唑兰和头孢克定侧链酸合成研究，安徽医药，2011，15(3)：294-295.
[64]潘小国，吴宇，张惠等.硫化促进剂DM的合成.化学推进剂与高分子材料，1998，4:38-39.
[65] Geiser J F, Hopper R J. Preparation of2.2’-dithiobis(benzothiazole) in anaqueous/alcohol reaction medium. US4755607,1988-07-05.
[66] Kaplan J H, Kinstler, R C, et.al. Continuous process for preparingbenzothiazyl disulfide. US4482720,1984-11-16.
[67] Danuta G, Jerzy, S, Jerzy W, et.al. Manufacture of2,2'-dibenzothiazolyldisulfide using N-chloro amines as oxidants. PL151594B1,1990-09-28.
[68] Gejza B.2,2'-Dibenzothiazolyl disulfide. CS18257915,1980-04.
[69] Ermakov O A, Davydova G F. Shtyrkov V N, et.al. Optimum parameters ofthe oxidative dimerization of2-mercaptobenzothiazole by hydrogen peroxide.Journal of applied chemistry of the USSR,1977,50(2):349-353.
[70] Lubomir K, Zubica M. Method of2,2-dibenzothiazolyl disulfidepreparation.CS254947B11988-11-15.
[71] Sever S, Luminita S, Mihaela B, et.al. Process for preparation of2-benzothiazolyl disulfide by oxidation of2-mercaptobenzothiazole. RO106253B1,1993-03-31.
[72] Tazuma J J. Method of preparation dibenzothiazolyl disulfides. US4463178，1984-07-31.
[73] Graeber E L, Lindstrom M J. Process for the preparation of2,2’-dithiobis(benzothiazole). US4859778,1989-04-22.
[74]陈昭琼.电解氧化制备二硫化二苯并噻唑.湘潭大学自然科学学报，1991，13(1):90-94.
[75] Nolte W, Konigshofen H, Sicheneder A. Process for preparation ofdithiazolyl disulfide. US6124467,2000-09-26.
[76] Shah S T A, Khan K M, Fecker M, et.al. A novel method for the sytheses ofsymmetrical disulfides using CsF-Celite as a solide base. Tetrahedron Letters,2003,(44):6789-6791.
[77] Zengel H G, Bergfeld M, Eisenhuth L. Process for the preparation ofdithiazolyl disulfide. US4558135,1985-12-10.
[78] Evans B J, Doi J T, Musker W K. Fluorine-19NMR study of the reaction ofp-fluorobenzenethiol and disulfide with periodate and other selected oxidizingagents, J.Org.Chem,1990,(55):2337-2377.
[79] Wolber W, Oberthür. Process for the production of dithiazolyl disulfides，US6610857,2003-08-26.
[80] Kang T W, Moon W S, Choi Y W, et.al. Preparation of reactive Phosphates ofthiazolylacetic acid as intermediates for preparing cephalosporin antibioties.WO9612712(A1),1996-05-02.
[81]王荣耕.新型活性酯DAMA.精细与专用化学品，2004，12(l3):11-12.
[82]王荣耕.氨噻肟酸与AE-活性酯.精细与专用化学品，2001，9(l):18-19.
[83]薛尧森,头孢药物中间体的合成及其配合物的研究,[硕士学位论文],青岛,中国海洋大学,2006
[84]王新杨, MICA活性硫酯工艺研究,河南师范大学学报,2009，37(6):165-167.
[85] Furlenmeier A, Hubschwerlen C N, Hofheinz W, et al. Process for thepreparation of1-sulfo-2-oxoazetidine derivatives. EP0096297,1983-12-21.
[86] Kishimoto S, Tomimatsu K, Miyake A,et al. New cephem compounds,theirproduction and use as antibiotics. EP249170,1987-12-16.
[87]高世豪，孙成辉，赵信.2-(5-氨基-1,2,4-,噻二唑-3-基)-2-(Z)-甲氧亚胺基乙酸苯并噻唑硫酯的合成工艺改进，精细化工，2007，24(8):816-819.
[88]董庆，吴松，孙颖等.二硫化二苯并噻唑在β-内酰胺合成中的应用.华西药学杂志，1990，15(1):12-14.
[89]高世豪，高长权，赵信岐.2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚胺基乙酸苯并噻唑硫酯的合成，中国医药工业杂志，2008，39(9):645-646.
[90] Ishikawa T, Iizawa Y, Okonogi K, et al. Studies on anti-MRSA parenteralcephalosporins. I. Synthesis and antibacterial activity of7-[2-(5-amino-1，2，4-thadiazol-3-yl)-2(Z)-hydroxyiminoacetamido]-3-(substituted imidazo [1，2-b]pytidazinium-1-yl)methyl-3–cephem-4-carboxylates and related compounds.Journal of Antibiotics,2000,53(10):1053-1070.
[91] Kobe J, Stanovnik B, Tisler T. Synthesis of pyridazine derivatives.XV. Someelectrophilic substitutions on imidazo [1,2-b] pyridazines. Tetrahedron,1968,24(1):239-345.
[92] Stanovnik B, Tislei M. Synthesis of imidazo [1,2-b]-s-trazolo[3′,4′-f]pyridazine, a new tricyclic azaheterocycle. Tetrahedron. Letters,1966,(22):2403-2406.
[93] Stanovnik B, Tisler M. Synthesis of pyridazine derivatives VIII. Imidazo [1,2-b] pyridazines and some tricyclic aza analogs. Tetrahedron,1967,23(1):387-395.
[94] Fabio P F, Lanzilotti A E, Lang S A. Synthesis of carbon-14and deuteriumlabeled3-nitro-6-propoxyimidazo[1,2-b]pyridazine-an antiparasitic agent. Jouralof Labelled Comounds and Radiopharmaceuticals,1978,15(Suppl.Vol.):407-412.
[95] Fajgelj S, Stanovnik B, Tisler M. Transformations of3-benzoyl-6-chloroimdazo[1,2-b]pyridazine. Vestnik Slovenskega KemijskegaDrustva,1985,32(2):137-145.
[96] Thomas D T, Charles J, Charles H.Moudlators of interleukin-1receptor-associated kinase.US2011/0021513A1,2011-01-27.
[97] Raboisson P, Mekonnen B, Peet N P. Efficient preparation of imidazo[1,2-b]pyridazines under Swern oxidative conditions. Tetrahedron Letters,2003,44(14):2919-2921.
[98]康从民，张德华，吕英涛.6-氯咪唑并[l,2-b]哒嗪的合成，化学与生物工程，2009，26(12):25-27.
[99] Stanovnik B, Ti ler M, Kunaver M, et al. Aza-transfer reactions. A novelmethod for the conversion of monosubstituted hydrazine compounds intohydrocarbons. Tetrahedron Letters,1978,19(33):3059-3062.
[100] Maeda Y, Tsukamoto T. Preparation of6-chloroimidazo[1,2-b] pyridazinehydrochloride as intermediate for cephalosporins. JP2040387，1990-02-09.
[101] Fujiwara Y,Shundo T. Preparation of6-amino-3-chloropyridazine as materialfor cephalosporins. JP4077474,1992-03-27.
[102]付春．咪唑[l，2-b]哒嗪．精细与专用化学品，2005，13(5):14-15.
[103]张连第，郭成.咪唑并[1,2-b]哒嗪的合成研究，江苏化工，2005，33(4):48-50.
[104] Miyake A, Kondo M, Fujino M.3-Condensed imidazoliumcephemcompounds. US4864022,1989-09-5.
[105] Nishimura S, Fujiwara Y, Hidaka H. Production of7-aminocephalosporanicacid derivative. WO9793002,1997-10-23.
[106] Yoshida K, Nishimura S, Maeda Y. Crystal of cephalosporin derivative andits production JP19980305664.1998-11-04.
[107]刘保起，李明华，孙松.盐酸头孢唑兰的制备方法、盐酸头孢唑兰粉针剂及其制备方法. CN10126256，2008-09-17.
[108] Padmanabhan R, Ramesh KA, Sundaravadivelan S, et al. An improvedprocess for the preparation of cefozopran: WO2009138487,2009-11-19.
[109] Miyake A, Kondo M, Fujino M, et al. Antibacterial compounds, theirproduction and use. EP0203271,1993-05-26.
[110] Teraji T, Sakane K, Goto J, et al. Cephem compounds, processes for theirpreparation and pharmaceutical compositions containing them. EP0027599,1984-10-03.
[111]龚登凰，贾国宾，武仙英等.盐酸头孢唑兰的合成研究，现代化工，2011，31(增1):110-111.
[112]郭鹏.新型降压药佐芬普利与头孢唑兰中间体7ACP的合成研究,[硕士论文]，济南；山东大学,2005.
[113]杨石,盐酸头孢唑兰及其中间体的制备方法, CN101735245A,2010-06-16.
[114]夏成才,程冬苹,于文博等.第四代头孢研究进展及合成综述,应用化工,2005,34(3):137-140.
[115] Takanohashi K, Yoshida T, Fujii S. Thiazole derivatives. US4695639,1987-09-22
[116] Hebeisen P. Process for producing allyl aminthiazole acetate intermediates.US4888429,1989-12-19
[117]陆宏国，徐云根，任东等.咪唑并［1，2-b］哒嗪的制备,中国医药工业杂志，2006,37(12):809-810.
[118] Feuer H, White E H, Wyman J E. The reactions of maleic anhydride withhydrazine hydrate. J Am Chem Soc,1958,80(14):3790-3792.
[119] Mizzoni R H, Spoerri P E. Synthesis in the pyridazine series. I. Pyridazineand3,6-dichloropyridazine. J Am Chem Soc,1951,73(4):1873-1874.
[120]蔡靖佩，许惠中.马来酰肼的合成与应用,江苏化工，1996，24(1):16-17，26.
[121] Katrusiak A，Katrusiak A. Polymorph-specific chlorination ofmaleic-hydrazide. Journal of Molecular Structure,2003,647(1-3):203-210.
[122]李荣坡.抑芽丹-马来酰肼的合成工艺研究,中国化工学会农药专业委员会第九届年会论文集:1998,9,404-406.
[123] Miyake A, Kondo M, Fujino M. Antibacterial compounds, their productionand use. WO8605183,1986-09-12.
[124]杨兰.医药中间体DM的清洁生产工艺，[硕士学位论文],青岛:青岛科技大学，2007.
[125] Dean J A.兰氏化学手册，北京：科学出版社，2003，6-11
[126]祝远娇,陈祖芬,陈小鹏等.反应-与结晶耦合单离脱氢枞酸过程研究,高校化学工程学报,2008,22(3):395-400.
[127]徐正.医药等中间体从传统向精细/专用化发展，精细与专用化学品，2005，133(4):29.
[128]周梅，陈光耀，马民.改变溶媒体系对AE活性酯合成收率及质量的影响，山东医药工业，2001，20(5):5-6.
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